Genetic Control of Symmetry in the Eye

眼睛对称性的遗传控制

• 批准号: 7486851
• 负责人: Richard Lee Kelley
• 金额: $ 35.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486851
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; Adaptor Signaling Protein; Address; Apoptosis; Binding; Biochemical Genetics; C-terminal; Cell Death; Cell Survival; Cells; Complex; Data; Differentiation and Growth; Dorsal; Down-Regulation; Drosophila genus; Essential Genes; Etiology; Event; Eye; Eye Development; Family; Gene-Modified; Genes; Genetic; Genetic Models; Goals; Golgi Apparatus; Growth; Growth and Development function; Homeodomain Proteins; Human Genetics; Ligands; Lobe; Localized; Mammals; Mediating; Modeling; Molecular; Molecular Genetics; Mothers; Notch Signaling Pathway; Organ; Pathway interactions; Pattern; Phenotype; Phosphorylation; Phosphotransferases; Play; Primordium; Proteins; Regulation; Research Personnel; Retinal; Retinal Diseases; Role; Signal Transduction; Specific qualifier value; System; Testing; Transcription Coactivator; Transferase; Ubiquitin-Conjugating Enzymes; base; cell growth; early childhood; eye primordia; gene function; genetic analysis; imaginal disc; in vivo; morphogens; mutant; notch protein; novel; prevent; transcription factor; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Axial patterning in organ primordium is essential for its growth and development. The fruit fly, Drosophila, provides an ideal model for genetic analysis of dorsoventral (DV) patterning and growth of the eye primordium. Our goal is to utilize this powerful genetic system to identify key genes involved in early eye patterning and reveal the molecular mechanisms of genetic interactions underlying this important event which marks first lineage restriction in developing eye. In early eye imaginal disc, the DV patterning is established by initiation of expression of a dorsal selector gene, pannier (pnr), which controls the expression of wingless (wg) signaling gene and Iroquois family transcription factors. The dorsal genes antagonize the function of ventral genes including Lobe (L), Serrate (Ser) and fringe (fng). The interaction of these two groups of genes leads to preferential activation of Notch signaling at the DV border to induce growth and differentiation. One of the major questions to be addressed is the molecular genetic basis for such regulatory interactions. Based on antagonistic relationship between the dorsal and ventral genes, we propose that the major function of genes involved in DV patterning is to either promote or suppress the Pnr-mediated Wg signaling in the dorsal and ventral domains, respectively. These genes are further regulated by factors involved in the control of cell survival and/or cell growth. To test these hypotheses, we will analyze (i) relationship between L and Dpp in the negative regulation of Wg signaling, (ii) the function of L and Homothorax (Hth) in the control of eye growth and retinal fate determination, (iii) function of L and Cullin-4 ubiquitin ligase in the control of ventral cell survival, and (iv) the regulation of L function by Fng and Akt kinase in cell growth. Most of the genes studied here are highly conserved as they are present in higher mammals including humans, and genetic control of DV patterning is an important event during mammalian eye development. This study will help in revealing mechanisms of genetic interactions involved in early eye development. Thus, our study will also contribute to the understanding of mammalian eye development and etiology of early childhood retinal diseases.

描述（由申请人提供）：器官原基的轴向模式对其生长和发育至关重要。果蝇为背腹 (DV) 模式和眼原基生长的遗传分析提供了理想的模型。我们的目标是利用这个强大的遗传系统来识别参与早期眼睛模式的关键基因，并揭示这一重要事件背后的遗传相互作用的分子机制，该事件标志着眼睛发育中的第一个谱系限制。 在早期眼成象盘中，DV 模式是通过背侧选择基因 pannier (pnr) 的表达启动而建立的，该基因控制 wingless (wg) 信号基因和易洛魁家族转录因子的表达。背侧基因拮抗腹侧基因的功能，包括叶（L）、锯齿（Ser）和边缘（fng）。这两组基因的相互作用导致 DV 边界处的 Notch 信号优先激活，以诱导生长和分化。要解决的主要问题之一是这种调控相互作用的分子遗传学基础。 基于背侧和腹侧基因之间的拮抗关系，我们提出参与 DV 模式的基因的主要功能是分别促进或抑制背侧和腹侧区域中 Pnr 介导的 Wg 信号传导。这些基因进一步受到参与控制细胞存活和/或细胞生长的因素的调节。为了检验这些假设，我们将分析 (i) L 和 Dpp 在 Wg 信号传导负调节中的关系，(ii) L 和同胸 (Hth) 在控制眼睛生长和视网膜命运决定中的功能，(iii) L 和 Cullin-4 泛素连接酶在控制腹侧细胞存活中的功能，以及 (iv) Fng 和 Akt 激酶在细胞生长中调节 L 功能。 这里研究的大多数基因都高度保守，因为它们存在于包括人类在内的高等哺乳动物中，并且 DV 模式的遗传控制是哺乳动物眼睛发育过程中的一个重要事件。这项研究将有助于揭示早期眼睛发育中涉及的遗传相互作用的机制。因此，我们的研究也将有助于了解哺乳动物眼睛发育和幼儿视网膜疾病的病因学。